Group VIA phospholipase A2 mitigates palmitate-induced β-cell mitochondrial injury and apoptosis

Palmitate (C16:0) induces apoptosis of insulin-secreting β-cells by processes that involve generation of reactive oxygen species, and chronically elevated blood long chain free fatty acid levels are thought to contribute to β-cell lipotoxicity and the development of diabetes mellitus. Group VIA phospholipase A2 (iPLA2β) affects β-cell sensitivity to apoptosis, and here we examined iPLA2β effects on events that occur in β-cells incubated with C16:0. Such events in INS-1 insulinoma cells were found to include activation of caspase-3, expression of stress response genes (C/EBP homologous protein and activating transcription factor 4), accumulation of ceramide, loss of mitochondrial membrane potential, and apoptosis. All of these responses were blunted in INS-1 cells that overexpress iPLA2β, which has been proposed to facilitate repair of oxidized mitochondrial phospholipids, e.g. cardiolipin (CL), by excising oxidized polyunsaturated fatty acid residues, e.g. linoleate (C18:2), to yield lysophospholipids, e.g. monolysocardiolipin (MLCL), that can be reacylated to regenerate the native phospholipid structures. Here the MLCL content of mouse pancreatic islets was found to rise with increasing iPLA2β expression, and recombinant iPLA2β hydrolyzed CL to MLCL and released oxygenated C18:2 residues from oxidized CL in preference to native C18:2. C16:0 induced accumulation of oxidized CL species and of the oxidized phospholipid (C18:0/hydroxyeicosatetraenoic acid)-glycerophosphoethanolamine, and these effects were blunted in INS-1 cells that overexpress iPLA2β, consistent with iPLA2β-mediated removal of oxidized phospholipids. C16:0 also induced iPLA2β association with INS-1 cell mitochondria, consistent with a role in mitochondrial repair. These findings indicate that iPLA2β confers significant protection of β-cells against C16:0-induced injury.